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We had so many questions during our webinar on the genetics of pancreatitis, which can be viewed here, that we could not answer them all during the session. We didn’t want to leave questions unanswered, so here are Dr. Mark Haupt and Dr. David Whitcomb‘s answers to the questions we didn’t get to:
1. Why is it that a patient can have severe abdominal pain/varying other symptoms, increased enzymes (many times more than 20x normal) but never show any inflammation on a CT scan (the patient has recurrent acute pancreatitis and does not consume alcohol)?
There are some instances in which patients have rare genetic conditions in which they don’t develop or demonstrate the typical fibrosis associated with pancreatitis. These include kidney disease, celiac disease, inflammatory bowel disease, other systemic inflammatory conditions, diabetes, chronic alcoholism, chronic infections or medications. A thorough medical history is required to evaluate these different causes to ensure the correct diagnosis is made.
In addition, some patients, unfortunately, have a poorly defined pain syndrome that may have a genetic component. A small amount of inflammation causes severe pain, and the best treatment is not yet known–but there is a lot of interest in figuring it out!
2. What do you believe the chances are that a drug for hereditary pancreatitis will be developed to cure diseases similar to the cystic fibrosis drug, Kalydeco?
Development of a pancreatitis-specific medication is possible. With the efforts of Mission: Cure, the National Pancreas Foundation, the American Pancreatic Association and all the scientists and clinicians focused on this disease, a drug should be developed or potentially repurposed for pancreatitis. Drug development is a long process. However, there are many things we have learned from the cystic fibrosis-ivacaftor experience that may accelerate the process.
There are some exciting possibilities that a drug or drugs will be developed in the next few years – but the time between discovery and patient use can be long. Ariel Precision Medicine is specifically dedicated to immediately linking patients with new treatments or clinical trials where these drugs are being testing in humans, and letting the patients know.
3. My GI (who was able to diagnose my chronic pancreatitis 2 years ago after years of misdiagnoses) tried to get me tested for Genetic CP. My cause is unknown, and I am currently diagnosed as “Idiopathic.” My insurance denied the testing, even with appeal, as it was “too dangerous with unknown outcomes.” Any suggestions to move the insurance company forward?
As discussed in the webinar, unfortunately there is a misperception that pancreatitis is all alcohol related. There is a major education gap that needs to be closed. Being persistent with your insurance company and working with your provider, and the testing company, to deliver the information needed to get coverage is what is required. This can take a long time. There are risks with genetic testing, but these are not unique to pancreatitis. Ensuring you fully understand the risks and benefits of testing prior to testing is important. A genetic counselor can help with this. The best advice is to keep trying, work through the appeal process, have your provider talk with the insurance company and explain why this will help his or her management of your condition. It’s not easy but it can be done.
4. I have 7-year-old twins (boy and girl). Both have PRSS1 mutation (from me-I’ve never had pancreatitis). My daughter was extremely ill and had TPIAT at 4 years old. My son had his first acute pancreatitis attack in September 2016. He had another attack in January 2017. In March 2017, his pan showed signs of chronic pancreatitis. Since that time, he has had two attacks that I have treated at home. Given that we are several years away from development of precision medicine, what is the best course of treatment? We are currently doing nothing.
Continue to follow up closely with your care provider. Given your family’s history, evaluation at a center familiar with TPIAT in pediatric patients would be advised. They will be able to give you the best guidance on monitoring and follow up. It is stories like this that continue to motivate physician-researchers to push toward better treatments every day.
5. How does MTHFR affect the pancreas? I have a mutation and know how it affects other things, but no one has ever said anything about how it may affect the pancreas. I have not had any genetic testing done specifically for pancreatitis as insurance does not cover such testing.
Abnormalities in MTHFR may be associated with inflammation and oxidative stress. Such processes have been described in pancreatitis. There are a few reports of patients with pancreatitis who have MTHFR variants. These studies are limited so no direct association can be linked. Additionally, patients in the studies who had MTHFR variants also had environmental exposures like smoking and alcohol use and other factors like obesity. This again demonstrates the complexity of pancreatitis. Regarding insurance coverage, there is variability with different payers and plans, but some coverage can be obtained.
6. Any suggestions for getting insurance to agree to genetic testing? Mine has been denied, even though I have 2 children with PRSS1.
In cases where there is a known variant, testing can be done for only that variant. This approach might be helpful with insurance as the cost may be less than a panel that evaluates many genes. These costs vary from lab to lab. Most of the work required is the upfront cost of getting the DNA out of the cells. That has to be done no matter what kind of sequencing is done. But, asking the insurance company if only looking at the specific variant your children carry may be a way to move forward with them.
7. Dr. Whitcomb mentioned 5 types of pain. What are they?
There are five different patterns of pain: 1) Episodes of mild to moderate pain, usually controlled by medication. 2) Constant mild to moderate pain usually controlled by medication. 3) Usually pain free with episodes of severe pain. 4) Constant mild pain plus episodes of severe pain. 5) Constant severe pain that does not change.
8. Is there a link between the SPINK1 gene and Type 2 diabetes?
There is not a lot of data that specifically looks at the question of Type 2 Diabetes and SPINK1 variants. The data is mixed. However, there is an elevated risk of diabetes in patients with chronic pancreatitis. Pancreatitis may also result in pancreatogenic diabetes, which is known as Type 3C Diabetes. Identifying this form of diabetes is important because the treatment is different.
9. Both of my children had genetic testing, I believe through Ambry. Would that testing include variant information?
Yes. Ambry has a Hereditary Pancreatitis genetic testing panel. A variant is another term for mutation. In general, the genetics community is moving away from using the term mutation and using the term variant.
10. When Dr. Whitcomb says that the smartphone is the key to getting to precision medicine, is there a certain app we should be looking for, or is this an area Mission: Cure might be looking to invest in to move this theory along?
Dr. Whitcomb: ARIEL Precision Medicine’s platform is available now. The secure ARIEL portal can be reached from a smartphone’s web browser. It is not a separate app but it is possible to have an icon on the phone that, when pushed, goes to the portal log-in page. (Disclosure: Dr. Whitcomb is a co-founder of ARIEL Precision Medicine.)
Mission: Cure: We are excited about the ARIEL platform and are also exploring use of wearables and other apps to measure symptoms such as pain and digestive function in a rigorous way that can be used both for patients to problem-solve with their doctors and to test the impact of new therapies in clinical trials.
11. I currently have CP but care is at a halt. Basically, I am told there is nothing further that can be done—that it will just get worse. I am on enzyme regimen and pain Rx. My question is it wise to go further into other testing or treatment or genetic testing?
Additional testing may be appropriate to see what complications of pancreatitis you’re at most risk for. Genetic testing can also determine if you have hereditary pancreatitis. In some cases, surgical options may be available. There is also testing for how your body handles medications called Pharmacogenomics. This can help figure out which pain medications might be best for you and which ones to avoid, or if any changes to your dose are needed.
It is also important to maintain a healthy lifestyle. Exercise helps in several ways. Adding antioxidants has proven to be effective in one well-done study (Shalimar, Midha S, Hasan A, Dhingra R, Garg PK. Long-term pain relief with optimized medical treatment including antioxidants and step-up interventional therapy in patients with chronic pancreatitis. J Gastroenterol Hepatol. 2017;32(1):270-7. PMID:27061119). Coffee (caffeine) may be protective, and red meat may have a little risk. Supporting research is also a good bet!
12. We have a strong family history of the PRSS1 genetic anomaly. I have a son who has no symptoms, but his brother, mother, cousin and uncle all are positive and suffer from RAP/CP. Would you recommend having the asymptomatic son tested?
Testing unaffected siblings in cases like this is a challenging decision. As discussed, the impact, or penetrance, of variants is variable. In cases of PRSS1 associated hereditary pancreatitis, the penetrance is 80%. Depending on the variant, the penetrance can be highly variable. Watching for early signs and symptoms and working with a specialist will be important.
13. If a patient has had genetic testing and a PRSS1 gene mutation discovered, would a genetic counselor still be helpful?
Genetic counselors are an incredible resource. Post-test genetic counseling is helpful to aid in identifying other family members who may be at risk, provide counseling on the meaning of the results and discuss if other testing is needed. The American College of Medical Genetics suggests that appropriate genetic counseling occurs before and after each genetic test.
14. Do the doctors consult with physicians in Canada? I’ve just had my genetics testing sent in within the last couple of weeks. 10 bouts of acute pancreatitis in the past two and half years, 14 since 2000. They have not been able to find any cause.
We are happy to discuss our work with anyone. Genetic testing laboratories will have different policies and abilities to process international samples.
15. I am at end stage chronic pancreatitis after being diagnosed 22 years ago as a child. I am only 28. I did test positive for PRSS1. How does that help me now in terms of treatment?
Much of this depends on the specific PRSS1 variant. Some PRSS1 variants are associated with Hereditary Pancreatitis and some are only mild risk factors. Knowing this information can help your care team monitor for specific complications, screen for pancreatic cancer, and consider other interventions including a TPIAT.
16. My son is 23. He has had some genetic testing and did test positive for the PSSR1 gene (from one parent). We went to Cleveland Clinic and the physician stated there wasn’t much they could do other than removing the pancreas as a last resort. Does this seem right? I’m worried that we need to be taking more steps, but not sure what and where to turn.
Working with a multidisciplinary team experienced in pancreatitis care is important for cases like this. TPIAT is a major surgery but can provide relief in patients for whom the procedure is appropriate. Evaluation at a center experienced in TPIAT may be helpful in understanding what treatment options are available. Avoiding alcohol and tobacco and following a healthy diet are also of benefit.
17. Has there been any research in epigenetics in association with pancreatic disease.
Yes. There has been a significant amount of work evaluating inflammation and cell injury. Evaluating the risk or progression to pancreatic cancer has been investigated in this manner.
18. I have a mutation of the PalB2 gene. Is this associated with CP?
PALB2 has been described in patients with pancreatic cancer. There are currently no published reports associating PALB2 with chronic pancreatitis. Pancreatitis may be a presenting sign of pancreatic cancer. In patients who develop new onset of pancreatitis above 40 years of age, pancreatic cancer should be a consideration.
19. Do you know if strep throat is related to pancreatitis?
Infections, especially certain viral infections, can cause acute pancreatitis. The viruses associated with pancreatitis include coxsackie, mumps, hepatitis B, cytomegalovirus, and herpes simplex as well as others. Bacterial infections associated with pancreatitis include mycoplasma, legionella, leptospira and salmonella. Other infectious causes have been reported. Streptococcal pharyngitis (Strep throat) has not been associated with acute pancreatitis. Strep throat is incredibly common. Meaning, the two could occur at the same time but not meaning one causes the other.
20. My 12-year-old recently tested positive for SPINK1, after many years of undiagnosed Pancreatitis episodes. It seems research related to SPINK1 is at its infancy, perhaps due to lower incidence compared to CFTR and PRSS1? Is that factual, and are you aware if there is current research related to SPINK1?
SPINK1 was first characterized in pancreatitis patients in 2000, though the enzyme had been identified much earlier. SPINK1 variants can cause a familial form of pancreatitis, sometimes the symptoms of which may be as severe as hereditary pancreatitis. SPINK1 variants are present in about 2% of the general population, but are seen in about 20-25% of patients with pancreatitis. In. general, SPINK1 tends to modify the course of the disease, meaning the age of onset, the progression of the disease etc…In general, we see SPINK1 variants plus something else. As the understanding of pancreatitis is evolving, the role of SPINK1 is becoming more clear. The INSPPIRE group is doing a significant amount of work evaluating the role of genetic factors in children with pancreatitis
21. My ten-year-old son has recently been diagnosed with chronic pancreatitis. Our doctor suspects lipo lipase deficiency disorder. She has told us that she will wait until the pancreas burns out. Is that normal?
Lipoprotein lipase can result in a condition called Familial Chylomicronemia Syndrome, also known as FCS. FCS causes extremely high levels of fat in the blood. These high levels of fat can cause pancreatitis. There are drugs that are in development for FCS and there are treatment strategies. If FCS is the cause of the pancreatitis, evaluation by a physician experiences in FCS is needed to try and prevent any further damage to the pancreas. This highlights the importance of understanding the cause of the pancreatitis to get the right treatment as soon as possible. A more comprehensive genetic evaluation may be needed, one that includes both pancreatitis genes and lipid genes since the results may affect the approach to therapy.